Inhibition of CSRP2 Promotes Leukemia Cell Proliferation and Correlates with Relapse in Adults with Acute Myeloid Leukemia

Shujuan Wang; Yu Zhang; Yajun Liu; Ruyue Zheng; Zhenzhen Wu; Yi Fan; Mengya Li; Menglin Li; Tao Li; Yafei Li; Zhongxing Jiang; Chong Wang; Yanfang Liu

doi:10.2147/OTT.S281802

Inhibition of CSRP2 Promotes Leukemia Cell Proliferation and Correlates with Relapse in Adults with Acute Myeloid Leukemia

Onco Targets Ther. 2020 Dec 7:13:12549-12560. doi: 10.2147/OTT.S281802. eCollection 2020.

Authors

Shujuan Wang^#¹, Yu Zhang^#¹, Yajun Liu², Ruyue Zheng¹, Zhenzhen Wu¹, Yi Fan¹, Mengya Li¹, Menglin Li¹, Tao Li¹, Yafei Li¹, Zhongxing Jiang¹, Chong Wang¹, Yanfang Liu¹

Affiliations

¹ Department of Hematology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, People's Republic of China.
² Department of Orthopaedics, Brown University, Warren Alpert Medical School/Rhode Island Hospital, Rhode Island, RI, USA.

^# Contributed equally.

Abstract

Background: Relapse is a major obstacle in the treatment of acute myeloid leukemia (AML). Reﬁnement of risk stratiﬁcation may aid the identiﬁcation of patients who are likely to relapse. Abnormal cysteine and glycine-rich protein 2 (CSRP2) has been implicated in various cancers, but its function remains unclear. The purpose of this study was to explore the role of CSRP2 in predicting adult AML recurrence.

Methods: RT-PCR was used to detect the expression of CSRP2 in 193 newly diagnosed adult AML patients and 44 healthy controls. The competitive risk model was used to calculate the cumulative incidence of relapse rate (CIR), Kaplan-Meier to calculate the relapse-free survival rate (RFS), and the Cox regression model to perform multivariate analysis. Viral transfection was used to construct AML cell lines with stable knockdown of CSRP2, CCK8 to detect proliferation and drug resistance, flow cytometry to detect cell cycle and apoptosis, and Western blot to detect key molecules in signaling pathways.

Results: CSRP2 transcript levels were higher in 193 adult AML compared with 44 healthy controls. In 149 patients who achieved complete remission, those with high CSRP2 transcript levels displayed a lower 2-year CIR and higher 2-year RFS, especially when receiving only chemotherapy. In multivariate analysis, a high CSRP2 transcript level was independently associated with a better RFS. Knockdown of CSRP2 promoted proliferation and cell cycle progression, and reduced chemosensitivity. Western blot analysis showed upregulation of p-AKT and p-CREB in CSRP2-knockdown AML cell lines. Inhibition assays suggested these two signaling pathways participated in the CSRP2-mediated proliferation effects in AML cell lines.

Conclusion: In summary, CSRP2 correlates with relapse in adult AML. Down-regulation of CSRP2 could promote the proliferation of AML cell lines by regulating the AKT and CREB signaling pathways. Therefore, CSRP2 may provide prognostic signiﬁcance and potential therapeutic targets in the management of AML.

Keywords: acute myeloid leukemia; cAMP-regulatory element-binding protein; cysteine and glycine-rich protein 2; proliferation; relapse.

Grants and funding

This work was supported by the National Natural Science Foundation of China [grant number 81800137 and U1804191] and Henan Medical Science and Technology Research Project (grant number 2018020068).